The study has a double-blind, cross-over, placebo-controlled design. During Session X, the subjects will receive an intravenous bolus dose of fentanyl (150 mug/70 kg) at time t = 0 during the background of an iv naloxone infusion (from t = -30 min until the end of the study; naloxone dose = 3 mg bolus followed by 3 mg/h). Next at 5-15 min intervals the response to 48-50 oC heat pain stimulus (using the TSA II device, Medoc, Israel) applied to the lower arm will be obtained. The measured response is a Visual Analogue Score (range 0 – 10 cm). During Session Y, the fentanyl infusion and heat pain measurements are identical to those of session X but now the background infusion is placebo (NaCl 0.9%). Duration of both sessions is 300 min. The sequence of session will be randomized. The naloxone/placebo treatment is blinded to the researcher and the subjects. All subjects will participate in both sessions, which will be at least 2 weeks apart.

- Primary outcome

Pain relief in response to a heat pain stimulus to the arm

- Secondary outcome

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- Timepoints

One session lasts 5-6 hours. Each subject will participate twice, one without and with a background infusion (naloxone/placebo)

Previously, we showed that iv fentanyl produces analgesic responses in the heat pain test. This stands in sharp contrast with data from a different protocol in which we observed that another opioid (M6G) caused hyperalgesic responses using the heat pain test.

It may well be that opioids cause a balanced effect via activation of opioid and non-opioid receptors. The latter possibly being NMDA-receptors. While the analgesic effect my dominate in some opioids (due to activation of opioid receptors with little activation of NMDA receptors), other opioids may cause hyperalgesic responses due to a shift in the balance towards the NMDA-receptor activation.

In this study we will focus on this latter hypothesis. If true, all opioids will cause hyperalgesic responses when the opioid receptor is blocked. We will perform fentanyl analgesic responses with and without naloxone infusion. Furthermore we will add a placebo group allowing us to perform the study in a double-blinded fashion.

Pain will be measured using the heat pain and electrical pain tests. These methods have been shown to be very safe and previously we very successful is discerning various opioid-related phenomena, such as sex differences in opioid analgesia using these methods.